Abstract Background Anaphylaxis is the most severe form of acute systemic and potentially life-threatening reactions triggered by mast and basophilic cells. Recent studies show a worldwide incidence between 50 and 112 occurrences per 100,000 person-years. The most identified triggers are food, medications, and insect venoms. We aimed to analyze triggers and clinical symptoms of patients presenting to a Swiss university emergency department for adults. Methods Six-year retrospective analysis (01/2013 to 12/2018) of all patients (> 16 years of age) admitted with moderate or severe anaphylaxis (classification of Ring and Messmer ≥ 2) to the emergency department. Patient and clinical data were extracted from the electronic medical database of the emergency department. Results Of the 531 includes patients, 53.3% were female, the median age was 38 [IQR 26–51] years. The most common suspected triggers were medications (31.8%), food (25.6%), and insect stings (17.1%). Organ manifestations varied among the different suspected triggers: for medications, 90.5% of the patients had skin symptoms, followed by respiratory (62.7%), cardiovascular (44.4%) and gastrointestinal symptoms (33.7%); for food, gastrointestinal symptoms (39.7%) were more frequent than cardiovascular symptoms (36.8%) and for insect stings cardiovascular symptoms were apparent in 63.8% of the cases. Conclusions Average annual incidence of moderate to severe anaphylaxis during the 6-year period in subjects > 16 years of age was 10.67 per 100,000 inhabitants. Medications (antibiotics, NSAID and radiocontrast agents) were the most frequently suspected triggers. Anaphylaxis due to insect stings was more frequently than in other studies. Regarding clinical symptoms, gastrointestinal symptoms need to be better considered, especially that initial treatment with epinephrine is not delayed.

L’immunothérapie allergénique est une méthode de traitement causale, efficace et bien tolérée des allergies respiratoires, avec un bénéfice en termes de prévention secondaire, en particulier pour les enfants et les jeunes.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

BACKGROUND:Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVES:This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS:Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed. RESULTS:A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSIONS:This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

AIMS OF THE STUDY: Anaphylaxis is a medical emergency and requires prompt treatment to prevent life-threatening conditions. Epinephrine, considered as the first-line drug, is often not administered. We aimed first to analyse the use of epinephrine in patients with anaphylaxis in the emergency department of a university hospital and secondly to identify factors that influence the use of epinephrine. METHODS: We performed a retrospective analysis of all patients admitted with moderate or severe anaphylaxis to the emergency department between 1 January 2013 and 31 December 2018. Patient characteristics and treatment information were extracted from the electronic medical database of the emergency department. RESULTS: A total of 531 (0.2%) patients with moderate or severe anaphylaxis out of 260,485 patients admitted to the emergency department were included. Epinephrine was administered in 252 patients (47.3%). In a multivariate logistic regression, cardiovascular (Odds Ratio [OR] = 2.94, CI 1.96-4.46, p <0.001) and respiratory symptoms (OR = 3.14, CI 1.95-5.14, p<0.001) were associated with increased likelihood of epinephrine administration, in contrast to integumentary symptoms (OR = 0.98, CI 0.54-1.81, p = 0.961) and gastrointestinal symptoms (OR = 0.62, CI 0.39-1.00, p = 0.053). CONCLUSIONS: Less than half of the patients with moderate and severe anaphylaxis received epinephrine according to guidelines. In particular, gastrointestinal symptoms seem to be misrecognised as serious symptoms of anaphylaxis. Training of the emergency medical services and emergency department medical staff and further awareness are crucial to increase the administration rate of epinephrine in anaphylaxis.

Purpose Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed drug hypersensitivity reaction with exanthema, eosinophilia, and organ manifestations. After culprit drug withdrawal, systemic corticosteroids (CS) are the most widely used treatment, often requiring high doses for months. Blocking the IL-5/IL‑5 receptor axis with mepolizumab, reslizumab, and benralizumab is a promising targeted treatment with a good safety profile and no immunosuppressive effect. The aim of this study is to summarize current experience with the anti-IL5/IL-5-receptor therapy in DRESS. Methods A retrospective analysis of all patients diagnosed with DRESS and treated with mepolizumab, reslizumab, or benralizumab in DRESS was performed. In addition, a PubMed–Medline search for publications on DRESS with anti-IL-5/IL‑5 receptor treatment was performed. Results Of the 14 cases identified, 6 patients were treated with mepolizumab, 6 with benralizumab, 1 patient with reslizumab, and 1 patient was switched from benralizumab to mepolizumab. The main indication for an IL‑5 blockade was a therapy-refractory course (7/14 [50.0%]), recurrent relapses (3/14 [21.4%]), and severe organ dysfunction (2/14 [14.3%]). In 13/14 (93%) cases, a rapid clinical improvement with suppression of eosinophilia and reduction of CS could be achieved. In all but two cases under mepolizumab (dose 100–600 mg) or reslizumab (dose according to body weight), two or more doses were necessary until resolution of DRESS. In 4/7 cases under benralizumab, a single 30 mg dose was sufficient. Conclusion Blockade of the IL-5/IL‑5 receptor axis appears to be a promising treatment in DRESS with fast clinical improvement, which may allow more rapid reduction of CS, and a good safety profile. In addition, a summary of recommendations on when to use blockade of the IL-5/IL‑5 receptor axis in DRESS treatment is provided.

Background: Clinical management of allergic diseases has been hampered by the lack of safe and convenient tests to reliably identify culprit allergens and to closely follow changes in disease activity over time. Because allergy diagnosis is a complex and laborious multistep procedure, there is an urgent need for simpler but still functionally accurate ex vivo assays allowing objective diagnosis, substantiating treatment choices, and quantifying therapeutic responses. Objective: In this study, we sought to develop a novel functional cell-based assay that relies on passive sensitization of allergic effector cells with patient serum, circumventing current limitations in allergy diagnosis. Methods: We genetically engineered a conditional homeobox B8 (Hoxb8)-immortalized progenitor line from the bone marrow of mice that are transgenic for the human high-affinity IgE receptor (Fc epsilon RIa). These cells can be reproducibly differentiated into mature Hoxb8 mast cells within 5 days of culture in virtually unlimited numbers. Results: We demonstrate that the established Hoxb8 mast cell assay can be used to accurately measure total IgE levels, identify culprit allergens, longitudinally monitor allergen-specific immunotherapy, and potentially determine the time point of tolerance induction upon allergen-specific immunotherapy in patients with allergy. To facilitate the analysis of large testing volumes, we demonstrate a proof-of-concept for a high-throughput screening application based on fluorescent cell barcoding using the engineered Hoxb8 mast cells. Conclusions: Our results indicate that this novel mast cell assay could represent a valuable tool to support clinicians in the identification of IgE-mediated allergies and in the quantification of treatment efficacy as well as duration of therapeutic response.

Objective: Fatigue is one of the most disabling and difficult to treat symptoms of autoimmune diseases and frequently presents in people with multiple sclerosis (PwMS). Hypogammaglobulinemia for immunoglobulin G (IgG) affects approximately 8-25% of PwMS. We performed a retrospective analysis to investigate the association of MS-fatigue and IgG hypogammaglobulinemia. Methods: PwMS, treated at Eginition University Hospital Athens or at the University Hospital Bern, were included (n = 134 patients (Bern n = 99; Athens n = 35)). Mann Whitney U-test (MWT), ANOVA test, Chi2 test and multivariable linear regression models were run. Results: 97/134 (72.4%) PwMS reported fatigue. In the multivariable linear regression analysis, IgG serum concentration (-1.6, 95%CI -2.7 --0.5, p = 0.006), daytime sleepiness (0.8, 95%CI 0.2-1.4, p = 0.009), and a depressive mood (1.1, 95%CI 0.8-1.4, p < 0.001) were significantly associated with fatigue. The impact of IgG serum concentration (-2.9 95%CI-4.7 --1.1,p = 0.002) remained significant also in the subcohort of PwMS without depressive symptoms or daytime sleepiness. Conclusions: We found an association between IgG hypogammaglobulinemia and fatigue in PwMS (Level of Evidence IV), which might be translated to other autoimmune diseases. It bears a potential therapeutic conse-quence considering IgG supplementation strategies, if our finding can be validated prospectively.

OBJECTIVES:Although mRNA-based vaccines against SARS-CoV-2 induce a robust immune response and prevent infections and hospitalizations, there are limited data on the antibody response in individuals with humoral immunodeficiency. The aim of this study was to evaluate the humoral immune response after two vaccine doses with BNT162b2 or mRNA-1273 in patients with humoral immunodeficiency disease. METHODS:This cross-sectional study assessed 39 individuals with hypogammaglobulinemia under immunoglobulin replacement therapy. IgG anti-SARS-CoV-2 spike protein antibodies (anti-S) were measured 4 weeks to 4 months after two doses of an mRNA vaccine against SARS-CoV-2. The proportion of patients, who developed a humoral immune response to the spike protein were evaluated and compared to 19 healthy controls. RESULTS:After vaccination with two vaccine doses, 26/39 patients (66.7%) with humoral immunodeficiency disease and all healthy controls developed anti-S. In subjects with baseline IgG <3 g/l, only 1/5 (20%) showed a humoral immune response. 10 out of 26 with CVID (38.5%) and 7/9 under immunosuppressive drugs (77.8%) developed no immune response (13 subjects with no response) compared to 0/19 in healthy controls. Subgroup analysis in patients without immunosuppressive drugs revealed lower anti-S in patients with moderate to severe humoral immunodeficiency disease: baseline IgG <3 g/l: 12.0 AU/ml (95%CI 12.0-125.0), baseline IgG 3-5 g/l: 99.9 AU/ml (95%CI 14.4-400.0), baseline IgG >5 g/l: 151.5 AU/ml (95%CI 109.0-400.0), healthy controls 250.0 AU/ml (95%CI 209.0-358.0), p = 0.007. CONCLUSION:In most patients with mild to moderate humoral immunodeficiency we found only slightly lower anti-S antibodies compared with healthy controls after two vaccine doses with BNT162b2 and mRNA-1273. However, in patients with a decreased baseline IgG below 3 g/l and/or under immunosuppressive drugs, we found severely impaired humoral immune responses.

Nahrungsmittelallergien (NMA) sind relativ haufige Feststellungen im Praxisalltag. Es gilt zwischen primaren und sekundaren NMA zu unterscheiden.

Allergies to gadolinium-based contrast agents (GBCAs) are rare and manifest usually as an immediate drug hypersensitivity reaction (DHR), compatible with an immunoglobulin E (IgE)-mediated mechanism.Although the molecular structures of GBCA show some similarities and are either linear or macrocyclic, the frequency and pattern of cross-reactivity remain unclear.However, cross-reactivity has been described.The aim of this investigation was to assess cross-reactivity in patients with GBCA allergy based on skin tests and exposure.We retrospectively evaluated a total of 28 cases with a proven allergy to a GBCA, including 11 from the database of the allergy division of the Inselspital, Bern and 17 published cases from the literature, retrieved with a PubMed-MEDLINE search.The majority of cases were immediate DHR, with 8/11 cases from the database (72.7%) and 16/17 published cases (94.1%).In both groups macrocyclic GBCA were most often identified as causative drugs.A cross-reactivity based on skin test results was found in 2 out of 11 database cases (18.2%) and in 6 out of 17 literature cases (35.3%).Cross-reactivity occurred within macrocyclic GBCA in 1/11 database cases and 3/17 literature cases, and included both macrocyclic and linear GBCA in 1/11 and 4/17 subjects.There was no cross sensitization among linear GBCA.Skin testnegative GBCA were well tolerated, even in cases with sensitization to linear and macrocyclic GBCA.Overall, cross-reactivity in GBCA allergy is rare (approximately 29%), and may occur among macrocyclic GBCA or in between macrocyclic and linear GBCA.IgE to linear GBCA seems to be rarely cross-reactive.Skin test is helpful in identifying safe alternatives, as no reaction to skin test-negative GBCA was observed.

Les allergies alimentaires (AA) sont relativement frequentes dans la pratique quotidienne. Il convient de faire la distinction entre AA primaire et secondaire.